Cystic fibrosis (CF) is one of the most common life-limiting autosomal recessive single gene disorders. Individuals with CF carry loss of function variants in each CF Transmembrane conductance Regulator (CFTR) gene. CFTR encodes a cAMP-activated chloride channel that ensures proper hydration and ion content of mucous secretions in the pulmonary airways and pancreatic ducts and maintains the correct concentration of chloride in sweat. Treatment of CF has taken a major step forward with the development of two classes of CFTR-targeted drugs. Ivacaftor (VX-770), a compound that potentiates the function of 33 variant forms of CFTR that are folded but inactive, has shown dramatic and lasting clinical effect. Lumacaftor (VX-809), a corrector compound, improves the folding of CFTR and demonstrates modest clinical efficacy in individuals with CF carrying the common disease-causing variant F508del. The success of these drugs indicate that we should be able to treat the vast majority of individuals with CF by targeting one or both of their CFTR variants. Several developments indicate that this goal is within reach. First, with near complete ascertainment of affected individuals by the CFTR2 project, we know that 520 variants account for 98.2% of CF alleles while the rest are `private', being reported in only one or two individuals worldwide. Second, in a major shift in policy, the Food and Drug Administration recently allowed expansion of the use of the CFTR-targeted drugs based on results of testing CFTR mutants expressed heterologously in immortalized cells. Third, we have developed and optimized a human airway cell line devoid of endogenous CFTR (termed CF8) for the functional assessment and drug response of heterologously expressed mutant forms of CFTR in a near native context. The overall goal of this application is to inform precision treatment by annotating every CF allele according to mechanism of effect, disease-liability and response to targeted drugs. This goal will be achieved by: 1) Determining disease mechanism, clinical consequences and drug response of CFTR variants to achieve annotation of 98.2% of all CF alleles reported to CFTR2; 2) Ensuring that the correct disease mechanism has been elucidated for missense variants that may also affect mRNA splicing or occur in cis with other potentially deleterious variants and 3) developing and testing predictive methods to determine disease liability and drug response of ~435 private missense variants in CFTR2. Upon completion of these aims, we estimate that 67,500 of the 70,000 individuals with CF worldwide will have mechanistic, clinical and drug response information for each CFTR variant they carry, 2,474 will have the same information for one variant leaving only 23 individuals with no information about either CFTR variant they carry. These data will be shared with the medical community and public on the CFTR2.org website. Our efforts to generate and test predictive approaches to variant annotation and drug response will provide information for rare and private CFTR variants that should inform similar efforts for all single gene disorders.